Process for the production of 2-oxa-3-one androstane derivatives

ABSTRACT

The present invention relates to processes for the production of 2-oxa-3-one androstane derivatives. The processes comprise reacting a 3-one androstane derivative with ozone to form a 2-oxa-3-one androstane derivative.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/447,457, filed Feb. 14, 2003, the entire content ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention generally relates to methods of producing2-oxa-3-one androstane derivatives.

BACKGROUND OF THE INVENTION

[0003] Methods of producing 2-oxa-3-one androstane derivatives such asoxandrolone (i.e., 17β-hydroxy-17α-methyl-2-oxa-5α-androstan-3-one) areknown. For example, U.S. Pat. No. 6,583,298 describes a process for thesynthesis of 17β-hydroxy-17α-methyl-2-oxa-5α-androstane-3-one, U.S.patent application Publication No. 2003/0032817 describes a process forthe synthesis of oxandrolone, and U.S. Patent No. 3,128,283 describes17-oxygenated oxa-steroids and intermediates thereto. However, as2-oxa-3-one androstane derivatives such as oxandrolone have varioustherapeutic uses, improved methods for producing 2-oxa-3-one androstanederivatives are desirable.

SUMMARY OF THE INVENTION

[0004] The methods of the present invention relate to producing2-oxa-3-one androstane derivatives from 3-one androstane derivatives. Inone aspect, a process is provided for the production of a 2-oxa-3-oneandrostane derivative comprising reacting a 3-one androstane derivativewith ozone to form a 2-oxa-3-one androstane derivative.

[0005] In another aspect of the invention, a process is provided for theproduction of oxandrolone comprising reacting mestanolone with ozone toform oxandrolone.

[0006] In yet another aspect, a process is provided for the productionof oxandrolone comprising reacting mestanolone with ozone in thepresence of hydrogen peroxide in a temperature range from about 1° C. toabout 50° C. for about 3 hours to about 5 hours with the ozone beingpresent in a mixture of oxygen and ozone.

[0007] In a further aspect, a process for the production of a2-oxa-3-one androstane derivative is provided comprising reacting a3-one androstane derivative of formula (IV)

[0008] with ozone to form a 2-oxa-3-one androstane derivative of formula(V)

[0009] wherein R¹, R², R³, R⁴, R⁵, and R⁶ are independently selectedfrom the following group: hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ ketone,phosphate, C₁₋₁₀ alkyl carboxylate, amino, hydroxy, thiol, C₁₋₁₀thioalkyl, C₁₋₁₀ alkoxy, substituted C₁₋₁₀ alkyl, and halogen.

DESCRIPTION OF THE INVENTION

[0010] The present invention relates to methods of producing 2-oxa-3-oneandrostane derivatives from 3-one androstane derivatives using ozone.

Definitions

[0011] Unless otherwise stated, the following terms used herein willhave the meanings given below:

[0012] “Alkyl” means a branched or unbranched saturated hydrocarbonradical preferably having from 1 to 20 carbon atoms.

[0013] “C₁₋₁₀ alkyl” means an alkyl group having from 1 to 10 carbonatoms.

[0014] “Ketone” means the group —(C)O(alkyl).

[0015] “C₁₋₁₀ ketone” means the group —(C)O(C₁₋₁₀ alkyl).

[0016] “Phosphate” means the group —O(P)O(OH)₂.

[0017] “Alkyl carboxylate” means the group —(C)OO-(alkyl).

[0018] “C₁₋₁₀ alkyl carboxylate” means the group —(C)OO—(C₁₋₁₀ alkyl).

[0019] “Amino” means the group —N(R)₂, wherein each R is independentlyselected from hydrogen, alky, and substituted alkyl, and preferably isindependently selected from hydrogen, C₁₋₁₀ alkyl, and substituted C₁₋₁₀alkyl.

[0020] “Hydroxy” means the group —OH.

[0021] “Thiol” means the group —SH.

[0022] “Thioalkyl” means the group —S-alkyl.

[0023] “C₁₋₁₀ thioalkyl” means the group —S—(C₁₋₁₀ alkyl).

[0024] “Alkoxy” means the group —O-alkyl.

[0025] “C₁₋₁₀ alkoxy” means the group —O—(C₁₋₁₀ alkyl).

[0026] “Halogen” means chlorine (Cl), bromine (Br), iodine (I), orfluorine (F).

[0027] “Substituted alkyl” means an alkyl group in which one or more ofthe hydrogens are independently replaced with an atom or group such as,for example, a ketone, a phosphate, an alkyl carboxylate, an amino, ahydroxy, a thiol, a thioalkyl, an alkoxy, a halogen, or any other atomor group that may be substituted for a hydrogen in an alkyl group.

[0028] “Substituted C₁₋₁₀ alkyl” means a C₁₋₁₀ alkyl group in which oneor more of the hydrogens are independently replaced with a substituentselected from the following group: C₁₋₁₀ ketone, phosphate, C₁₋₁₀ alkylcarboxylate, amino, hydroxy, thiol, C₁₋₁₀ thioalkyl, C₁₋₁₀ alkoxy, andhalogen.

[0029] “Androstane derivative” means a steroid having one or morechanges to the steroid structure of formula (I) shown below.

[0030] The one or more changes may be one atom substituted for a carbon(e.g., an oxygen substituted for the carbon at position 2) or may be anatom or group substituted for one or more hydrogens bonded to one of thecarbons of the steroid structure (e.g., an oxygen with a double bond(i.e., the group═O) substituted for the two hydrogens bonded to thecarbon in position 3). In addition, the one or more changes could be asubstitution of a double bond in the place of two hydrogen atomsseparately bonded to two different carbon atoms that are bonded to oneanother (e.g., a double bond could be substituted for a hydrogen atombonded to the carbon at position 16 and a hydrogen atom at position 17).The one or more changes may include independently replacing one or moreof the hydrogen atoms in the steroid structure with an atom or groupsuch as, for example, an alkyl, a ketone, a phosphate, an alkylcarboxylate, an amino, a hydroxy, a thiol, a thioalkyl, an alkoxy, ahalogen, a substituted alkyl, or any other atom or group that may besubstituted for a hydrogen in the steroid structure of formula (I).

[0031] “3-one androstane derivative” means an androstane derivativehaving an oxygen with a double bond substituted for the two hydrogensbonded to the carbon in position 3 of the steroid. A “3-one androstanederivative” may also have other changes as defined for an androstanederivative. For example, one or more of the carbons at positions 14-17may have one or both of their hydrogens replaced with a substituentselected from the following group: C₁₋₁₀ alkyl, C₁₋₁₀ ketone, phosphate,C₁₋₁₀ alkyl carboxylate, amino, hydroxy, thiol, C₁₋₁₀ thioalkyl, C₁₋₁₀alkoxy, substituted C₁₋₁₀ alkyl, and halogen. An example of a “3-oneandrostane derivative” is mestanolone, shown below as formula (II):

[0032] “2-oxa-3-one androstane derivative” means an androstanederivative having an oxygen atom substituted for the carbon in position2 of the steroid and having an oxygen with a double bond substituted forthe two hydrogens bonded to the carbon in position 3 of the steroid. A“2-oxa-3-one androstane derivative” may also have other changes asdefined for an androstane derivative. For example, one or more of thecarbons at positions 14-17 may have one or both of their hydrogensreplaced with a substituent selected from the following group: C₁₋₁₀alkyl, C₁₋₁₀ ketone, phosphate, C₁₋₁₀ alkyl carboxylate, amino, hydroxy,thiol, C₁₋₁₀ thioalkyl, C₁₋₁₀ alkoxy, substituted C₁₋₁₀ alkyl, andhalogen. An example of a “2-oxa-3-one androstane derivative” isoxandrolone, shown below as formula (III):

[0033] According to the present invention, a 2-oxa-3-one androstanederivative is produced by reacting a 3-one androstane derivative withozone. The 3-one androstane derivative may be in solution, and ispreferably in an aqueous solution. The ozone that is reacted with the3-one androstane derivative is preferably present in a mixture of ozoneand oxygen. In one embodiment, the reaction is conducted by bubbling amixture of ozone and oxygen through an aqueous solution of a 3-oneandrostane derivative. The reaction is preferably performed in anexplosion-proof vessel, although other reaction vessels could also beused to carry out the reaction.

[0034] The reaction of the 3-one androstane derivative with ozone ispreferably conducted in the presence of a peroxide. The peroxide may bean organic peroxide or an inorganic peroxide. One preferred inorganicperoxide is hydrogen peroxide (H₂O₂).

[0035] In one embodiment, the 3-one androstane derivative may be in anaqueous solution and a peroxide (e.g., hydrogen peroxide) may becontinuously added (e.g., by dropwise addition to the solution) suchthat the peroxide is present during the entire reaction period or aportion of the reaction period.

[0036] The reaction of a 3-one androstane derivative with ozone may becarried out over varying periods of time such as, for example, 1-24hours, preferably 2-12 hours, more preferably 3-5 hours. The reaction ofa 3-one androstane derivative with ozone may also be carried out invarying ranges of temperatures such as, for example, in a temperaturerange between about 1° C. to about 50° C., preferably in a temperaturerange between about 5° C. to about 40° C., more preferably in atemperature range between about 10° C. to about 30° C.

[0037] After performing the reaction, the reaction mixture containingthe 2-oxa-3-one androstane derivative may be isolated and/or purifiedaccording to known procedures. For example, when the reaction isperformed using an aqueous solution of a 3-one androstane derivative, anorganic solvent (e.g., methylene chloride) may be used to perform anextraction. If such an extraction is performed, the reaction solutionmay be diluted with water if desired. In addition, the reaction vesseland/or reaction mixture may be allowed to return to room temperature (ifnot already at room temperature) before isolating and/or purifying the2-oxa-3-one androstane derivative.

[0038] In one aspect, the 3-one androstane derivative is mestanolone(Formula (II) below), which is reacted with ozone to produce oxandrolone(Formula (III) below) as shown by the following reaction scheme:

[0039] The mestanolone (Formula (II)) is preferably in aqueous solutionand the ozone is preferably present as a mixture of ozone and oxygen.The reaction is preferably performed by bubbling the ozone/oxygenmixture through the aqueous solution of mestanolone. In addition, aperoxide (e.g., hydrogen peroxide) is preferably added continuously tothe reaction solution (e.g., by dropwise addition) while performing thereaction.

[0040] In another aspect, a 3-one androstane derivative of formula (IV)is reacted with ozone to produce a 2-oxa-3-one androstane derivative offormula (V) according to the following reaction scheme:

[0041] wherein R¹, R², R³, R⁴, R⁵, and R⁶ are independently selectedfrom the following group: hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ ketone,phosphate, C₁₋₁₀ alkyl carboxylate, amino, hydroxy, thiol, C₁₋₁₀thioalkyl, C₁₋₁₀ alkoxy, substituted C₁₋₁₀ alkyl, and halogen.

[0042] The 3-one androstane derivative of formula (IV) is preferably inaqueous solution and the ozone is preferably present as a mixture ofozone and oxygen. The reaction is preferably performed by bubbling theozone/oxygen mixture through the aqueous solution of the 3-oneandrostane derivative of formula (IV). In addition, a peroxide (e.g.,hydrogen peroxide) is preferably added continuously to the reactionsolution (e.g., by dropwise addition) while performing the reaction.

[0043] While the invention has been described in detail and withreference to specific embodiments thereof, it will be apparent to oneskilled in the art that various changes and modifications can be madewithout departing from the spirit and scope of the invention.

1. A process for the production of a 2-oxa-3-one androstane derivative,the process comprising reacting a 3-one androstane derivative with ozoneto form a 2-oxa-3-one androstane derivative.
 2. The process of claim 1,wherein the reaction is conducted in the presence of an organic orinorganic peroxide.
 3. The process of claim 2, wherein the peroxide ishydrogen peroxide.
 4. The process of claim 1, wherein the reaction iscarried out in a temperature range from about 1° C. to about 50° C. 5.The process of claim 1, wherein the 3-one androstane derivative isreacted with ozone for about 3 hours to about 5 hours.
 6. The process ofclaim 1, wherein the ozone that is reacted with the 3-one androstanederivative is present as a mixture of oxygen and ozone.
 7. A process forthe production of oxandrolone, the process comprising reactingmestanolone with ozone to form oxandrolone.
 8. The process of claim 7,wherein the reaction is conducted in the presence of an organic orinorganic peroxide.
 9. The process of claim 8, wherein the peroxide ishydrogen peroxide.
 10. The process of claim 7, wherein the reaction iscarried out in a temperature range from about 1° C. to about 50° C. 11.The process of claim 7, wherein the mestanolone is reacted with ozonefor about 3 hours to about 5 hours.
 12. The process of claim 7, whereinthe ozone that is reacted with the mestanolone is present as a mixtureof oxygen and ozone.
 13. A process for the production of oxandrolone,the process comprising reacting mestanolone with ozone in the presenceof hydrogen peroxide in a temperature range from about 1° C. to about50° C. for about 3 hours to about 5 hours, the ozone being present in amixture of oxygen and ozone.
 14. The process of claim 13, wherein themestanolone is present in an aqueous solution.
 15. A process for theproduction of a 2-oxa-3-one androstane derivative, the processcomprising reacting a 3-one androstane derivative of formula (IV)

wherein R₁, R₂, R₃, R₄, R₅, and R⁶ are independently selected from thefollowing group: hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ ketone, phosphate, C₁₋₁₀alkyl carboxylate, amino, hydroxy, thiol, C₁₋₁₀ thioalkyl, C₁₋₁₀ alkoxy,substituted C₁₋₁₀ alkyl, and halogen; with ozone to form a 2-oxa-3-oneandrostane derivative of formula (V)

wherein R₁, R₂, R₃, R₄, R₅, and R⁶ are as above in formula (IV).
 16. Theprocess of claim 15, wherein the reaction is conducted in the presenceof an organic or inorganic peroxide.
 17. The process of claim 16,wherein the peroxide is hydrogen peroxide.
 18. The process of claim 15,wherein the reaction is carried out in a temperature range from about 1°C. to about 50° C.
 19. The process of claim 15, wherein the 3-oneandrostane derivative of formula (IV) is reacted with ozone for about 3hours to about 5 hours.
 20. The process of claim 15, wherein the ozonethat is reacted with the 3-one androstane derivative of formula (IV) ispresent as a mixture of oxygen and ozone.
 21. The process of claim 20,wherein the reaction is conducted in the presence of hydrogen peroxide.